TY - JOUR T1 - Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density JF - Molecular Pharmacology JO - Mol Pharmacol SP - 413 LP - 424 DO - 10.1124/mol.115.102533 VL - 89 IS - 4 AU - Shanti Diwakarla AU - Erik Nylander AU - Alfhild Grönbladh AU - Sudarsana Reddy Vanga AU - Yasmin Shamsudin Khan AU - Hugo Gutiérrez-de-Terán AU - Leelee Ng AU - Vi Pham AU - Jonas Sävmarker AU - Thomas Lundbäck AU - Annika Jenmalm-Jensen AU - Hanna Andersson AU - Karin Engen AU - Ulrika Rosenström AU - Mats Larhed AU - Johan Åqvist AU - Siew Yeen Chai AU - Mathias Hallberg Y1 - 2016/04/01 UR - http://molpharm.aspetjournals.org/content/89/4/413.abstract N2 - Angiotensin IV (Ang IV) and related peptide analogs, as well as nonpeptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocyclic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N terminus of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09, and of Ang IV in either the extended or γ-turn conformation at the C terminus to human IRAP were predicted by docking and molecular dynamics simulations. The binding free energies calculated with the linear interaction energy method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity. ER -